Kidney cancer affects more than 55,000 people in the United States each year.

For years, kidney cancer specialists have puzzled over two seemingly contradictory research findings: Obesity is associated with an increased risk of kidney cancer, yet obese and overweight people have better odds of surviving kidney cancer than normal-weight people.

A new study by a team from Memorial Sloan Kettering has uncovered a possible biological explanation for the phenomenon known as the “obesity paradox.”

A genetic analysis of tumor samples from patients with renal cell carcinoma, a common form of kidney cancer, found normal-weight patients had higher expression of a gene associated with faster-growing tumors than obese patients. Previous studies have shown that the gene, FASN, is overexpressed in aggressive tumors in several types of cancer.

The activity of FASN may help to explain why obese kidney cancer patients tend to fare better than normal-weight patients, says epidemiologist Helena Furberg, a coauthor of the study. With less activity in a cancer-promoting gene, tumors in obese people may grow more slowly than in normal-weight people.

By understanding what drives the progression of these tumors, the research, published online in December in the Journal of the National Cancer Institute, could ultimately lead to better therapeutic strategies.

Metastatic Disease More Likely in Slim Patients

The study included 2,119 kidney cancer patients who underwent surgery at Memorial Sloan Kettering between 1995 and 2012. As had been noted in previous research, this study found that normal-weight people are more likely to have their cancer discovered at advanced stages than obese people.

Obese patients also had a 25 percent lower risk of cancer-related death than normal-weight patients. (Obesity is defined as a body mass index, or BMI, of 30 or greater; normal weight is a BMI of under 25. BMI is an estimate of body fat based on a person’s height and weight.)

But the team's analysis showed that obesity alone didn't explain the difference in the risk of death, Dr. Furberg notes. Instead, the risk of death was associated with the stage at which the cancer was detected — and normal-weight people were more likely to have metastatic disease at the time of diagnosis.

These findings led researchers to wonder if there was something different about the tumors themselves in obese patients versus normal-weight patients influencing the cancer's growth.

Honing In on the Tumor Genome

For answers, Dr. Furberg and her colleagues turned to The Cancer Genome Atlas (TCGA), a project funded by the National Institutes of Health to map the genetic mutations and alterations that occur in cancer cells.

The team's analysis of genetic data available through TCGA revealed an overexpression of the FASN gene in the tumors of normal-weight patients. “FASN is an oncogene, which are genes that are the gas pedal driving cancer progression,” Dr. Furberg says.

In a normal cell, FASN is involved in the regulation of fatty acids, or fat production and breakdown, explains urologic oncology fellow Ari Hakimi, a coauthor of the study. “Cancer cells hijack that mechanism, and use it to fuel growth,” Dr. Hakimi says.

Their findings suggest that obesity interferes with cancer cells' ability to hijack the mechanism, which may help prevent tumors from spreading quickly, Dr. Hakimi adds.

Yet researchers cautioned that their findings come with caveats. First, the team didn't prove that obesity causes decreased expression of FASN. Second, the findings shouldn't be interpreted as advice about weight management in kidney cancer patients, or how weight gain or loss might influence survival during the course of the disease.

Insights for Future Research

Instead, the findings will guide future research on the role of obesity and FASN in tumor growth. “Our study provides mechanistic insights into the obesity paradox,” Dr. Furberg says. “It gives researchers a different place to start in terms of understanding how body size influences patients' survival.”

Finally, even though obesity is associated with a lower risk of death from kidney cancer, the statistics don't speak to any individual's odds of survival, which are impacted by many factors.

“What this study indicates is a new granularity, or knowledge of cancer, and how the genetics of tumors impact the way in which tumors behave,” says kidney surgeon Paul Russo, the senior author of the study. “We are on the precipice of a better understanding of the things that power tumors, which could eventually lead to tailored treatments and novel strategies to stop tumors from spreading.”

This study was supported by the National Cancer Institute under grants CA082088 and U24CA143840, the Stephen P. Hanson Family Fund Fellowship in Kidney Cancer, and the Paula Moss Trust for the research into the cure and treatment of kidney cancer.

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